Noise-induced hearing loss is a problem of profound clinical significance, growing magnitude, and major societal impact, because opportunities for overexposure abound, and exposures that damage hearing are not necessarily painful. Loss of, or damage to, hair cells has long been considered the primary cause of noise-induced hearing loss, with degeneration of the auditory nerve occurring only as a secondary event. Recently, however, it has been shown that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of nerve terminals on hair cells and delayed degeneration of the auditory nerve. This primary auditory neuropathy suggests that noise-induced damage to the ear is considerably more widespread than is revealed by conventional threshold testing. Identifying molecular mechanisms of this novel phenomenon is our focus. Our working hypothesis is that the cell death cascade, and its upstream initiators, are different in primary and secondary auditory neuropathy. To test this hypothesis we propose, first, to better characterize the time course and nature of the primary neuropathy (Aim 1), and then to probe its mechanisms by combining a candidate-molecule approach (Aim 2) with a genome-wide quantitative survey using a new technology (Solexa deep sequencing Aim 3), which can detect rare transcripts and small changes in gene expression more reliably than conventional microarrays. These studies should help identify new molecular targets for diagnosis and therapeutic intervention for noise-induced hearing loss. CANDIDATE: The proposal describes a training program to develop Konstantina Stankovic to an independent physician scientist in otolaryngology. Career development activities include training and research to acquire the requisite skills necessary for a sustainable career in health-oriented scientific investigation. A mentoring team and an advisory committee of highly regarded scientists in the fields of acoustic trauma, neuroscience, molecular biology, genetics, and systems biology will guide the candidate in her transition to autonomy. This award will provide a foundation for the candidate to achieve her long-term career goal of developing new diagnostics and therapeutics for sensorineural hearing loss - a problem of major clinical significance for which curative treatments do not yet exist. This proposal addresses noise-induced primary auditory neuropathy, a potentially very common problem, and likely a major contributor to neural presbycusis (especially the problems with hearing in noisy environments) for which medical therapies do not exist, and amplification with hearing aids is of little help. By uncovering mechanisms of this primary neurodegeneration after temporary noise-induced threshold shift, the proposed studies should lay groundwork for future design of optimized therapies to prevent this degeneration and its associated impact on hearing performance.